The goal of this proposal is to develop nitric oxide releasing dendrimers to inhibit biofilm based periodontopathogens and associated periodontal disease. The rationale for pursuing this work is based on nitric oxide's broad spectrum antimicrobial activity, rapid diffusion through biofilms, short half-life (thus imparting local acton) and physiological role in the immune response to pathogens. The use of a macromolecular NO release scaffold enables us to maximize bactericidal activity while minimizing the cytotoxic impact on healthy oral cells and tissue. We will study the influence of dendrimer size/molecular weight, charge, exterior functionality, and NO release properties on pathogenic plaque bacteria killing. We will systematically study both dendrimer and nitric oxide penetration into in vitro models of oral plaque biofilms as a function of biofilm composition, maturity and mass. An established murine model for periodontal infection will be employed to evaluate how dendrimer composition and nitric oxide release influence inflammation, host immune response, and biofilm eradication.